Impaired cognition is aging represents the behavioral manifestation of specific pathologies and an as yet unknown comination of structural changes. We have previously demonstrated that the most reliable index of cognition in both postmortem and biopsied brain is synapse loss. The present proposal seeks to identify the underlying structural correlate to cognition in a well characterized population of Catholic nuns with mild cognitive impairment (MCI), as compared to cognitively normal and AD cases in the same cohort. We anticipate that some MCI cases will have preclinical AD, but not all. Regions selected for analysis subserve functions known to be affected in MCI and AD. The members of the religious orders study core represent a unique opportunity to examine individuals who have had recent antemortem cognitive assessment and well documented life history. We willuse postmortem brain tissue fromthe religious orders study core subjects to test the following hypotheses: 1) Deficits in premortem cognition, in both MCI and AD, willcorrelate with a reduction in synapse number and an increase in mean volume and area of remaining synapses in affected areas. 2) ApoE allele frequencey will be over represented in both AD and MCI, and have greater synapse and ChAT deficits, and will have less compensatory enlargement of residual synapses. 3) Deficits in regional synaptic density and synaptic plasticity (synaptophysin, GAP-43, SNAP-25) will correlate with premortem cognition and loss of these RNAs will be localized to dystrophic neurons with neurofibrillary pathology. These stuides will determine if synapse loss or reduced synapse-associated mRNAs, or reduced ChAT activity represents the first structural change in MCI individuals. The studies outlined will elucidate the specific structural and molecular deficits of synapse loss and will examine the role of classic markers of neurodegeneration in the manifestation of impaired cognition. Understanding status of synaptic connectivity in MCI brain will allow us to better evaluate the importance of pharmacological therapies, such as cholinergic agonists or in the treatment of cognitive impairment.